This project is concerned with the physiological and genetic regulation of drug resistance in Mycobacterium tuberculosis H37Ra, Mycobacterium bovis BCG, Mycobacterium avium, Mycobacterium farcinicum, Mycobacterium intracellulare and Mycobacterium kansasii and with genetic relationships among these pathogenic mycobacteria. The anti-tubercular drugs to be used include cycloserine, ethambutol, ethionamide, isonicotinic hydrazide, kanamycin, pyrazinamide, para-aminosalicylic acid, rifampin, streptomycin and viomycin. One phase of this project is concerned with developing methods to retard the emergence of drug resistant variants. Another phase of this project consists of a search for episomal or plasmid deoxyribonucleic acid (DNA) in pathogenic mycobacteria and for inactivation of antitubercular drugs by extracts of pathogenic mycobacteria. The widespread distribution of bacterial plasmids and episomal elements that confer drug resistance, enhance pathogenicity or invasiveness, expand physiological capabilities and/or confer the ability to engage in cell- cell recombination may limit of effectiveness in preventing, diagnosing and treating bacterial infectious diseases. In addition, nucleotide sequence homology among DNA samples from pathogenic mycobacteria will be assessed and attempts to transfer drug resistance and other genetic markers will be made. These studies should provide information about the emergence and spread of drug resistance in pathogenic mycobacterial populations and provide some data about the possibility that new mycobacterial pathogens are arising by genetic recombination.